Targeting TRIP13 in favorable histology Wilms tumor with nuclear export inhibitors synergizes with doxorubicin.

Wilms tumor (WT) is the most common renal malignancy of childhood. Despite improvements in the overall survival, relapse occurs in ~15% of patients with favorable histology WT (FHWT). Half of these patients will succumb to their disease. Identifying novel targeted therapies remains challenging in part due to the lack of faithful preclinical in vitro models. Here we establish twelve patient-derived WT cell lines and demonstrate that these models faithfully recapitulate WT biology using genomic and transcriptomic techniques. We then perform loss-of-function screens to identify the nuclear export gene, XPO1, as a vulnerability. We find that the FDA approved XPO1 inhibitor, KPT-330, suppresses TRIP13 expression, which is required for survival. We further identify synergy between KPT-330 and doxorubicin, a chemotherapy used in high-risk FHWT. Taken together, we identify XPO1 inhibition with KPT-330 as a potential therapeutic option to treat FHWTs and in combination with doxorubicin, leads to durable remissions in vivo.

Recommendations to Improve Services and Supports for Domestically Sex Trafficked Persons Derived from the Insights of Health Care Providers.

Health care providers are highly likely to encounter persons who have been domestically sex trafficked and, therefore, possess valuable insights that could be useful in understanding and improving existing services and supports. In-depth interviews were conducted with 31 health care providers residing and working in Canada's largest province, Ontario. Results were analyzed using Braun and Clarke's analytical framework. Across providers, a key theme was identified: "Facilitators to improve care", which was comprised of two sub-themes, "Address needs in service provision" and "Center unique needs of survivors". From these results, eight wide-ranging recommendations to improve services and supports were developed (eg, Jointly mobilize an intersectoral, collaborative, and coordinated approach to sex trafficking service provision; Employ a survivor-driven approach to designing and delivering sex trafficking services). These recommendations hold the potential to enhance services in Canada and beyond by reducing barriers to access and care, facilitating disclosure, aiding in recovery, and empowering those who have been domestically sex trafficked.

Effects of Age and Noise Exposure History on Auditory Nerve Response Amplitudes: A Systematic Review, Study, and Meta-Analysis.

Auditory nerve (AN) function has been hypothesized to deteriorate with age and noise exposure. Here, we perform a systematic review of published studies and find that the evidence for age-related deficits in AN function is largely consistent across the literature, but there are inconsistent findings among studies of noise exposure history. Further, evidence from animal studies suggests that the greatest deficits in AN response amplitudes are found in noise-exposed aged mice, but a test of the interaction between effects of age and noise exposure on AN function has not been conducted in humans. We report a study of our own examining differences in the response amplitude of the compound action potential N1 (CAP N1) between younger and older adults with and without a self-reported history of noise exposure in a large sample of human participants (63 younger adults 18-30 years of age, 103 older adults 50-86 years of age). CAP N1 response amplitudes were smaller in older than younger adults. Noise exposure history did not appear to predict CAP N1 response amplitudes, nor did the effect of noise exposure history interact with age. We then incorporated our results into two meta-analyses of published studies of age and noise exposure history effects on AN response amplitudes in neurotypical human samples. The meta-analyses found that age effects across studies are robust (r=-0.407), but noise-exposure effects are weak (r=-0.152). We conclude that noise-exposure effects may be highly variable depending on sample characteristics, study design, and statistical approach, and researchers should be cautious when interpreting results. The underlying pathology of age-related and noise-induced changes in AN function are difficult to determine in living humans, creating a need for longitudinal studies of changes in AN function across the lifespan and histological examination of the AN from temporal bones collected post-mortem.

The New Media Landscape and Its Effects on Skin Cancer Diagnostics, Prognostics, and Prevention: Scoping Review.

BACKGROUND: The wide availability of web-based sources, including social media (SM), has supported rapid, widespread dissemination of health information. This dissemination can be an asset during public health emergencies; however, it can also present challenges when the information is inaccurate or ill-informed. Of interest, many SM sources discuss cancer, specifically cutaneous melanoma and keratinocyte cancers (basal cell and squamous cell carcinoma). OBJECTIVE: Through a comprehensive and scoping review of the literature, this study aims to gain an actionable perspective of the state of SM information regarding skin cancer diagnostics, prognostics, and prevention. METHODS: We performed a scoping literature review to establish the relationship between SM and skin cancer. A literature search was conducted across MEDLINE, Embase, Cochrane Library, Web of Science, and Scopus from January 2000 to June 2023. The included studies discussed SM and its relationship to and effect on skin cancer. RESULTS: Through the search, 1009 abstracts were initially identified, 188 received full-text review, and 112 met inclusion criteria. The included studies were divided into 7 groupings based on a publication's primary objective: misinformation (n=40, 36%), prevention campaign (n=19, 17%), engagement (n=16, 14%), research (n=12, 11%), education (n=11, 10%), demographics (n=10, 9%), and patient support (n=4, 3%), which were the most common identified themes. CONCLUSIONS: Through this review, we gained a better understanding of the SM environment addressing skin cancer information, and we gained insight into the best practices by which SM could be used to positively influence the health care information ecosystem.

Professional Experiences and Career Trajectories of Mid- to Senior-Career Women Clinician-Scientists: A Qualitative Study.

Importance: Despite increasing evidence and recognition of persistent gender disparities in academic medicine, qualitative data detailing the association of gender-based experiences with career progression remain sparse, particularly at the mid- to senior-career stage. Objective: To investigate the role gender has played in everyday professional experiences of mid- to senior-career women clinician-scientists and their perceptions of gender-related barriers experienced across their careers. Design, Setting, and Participants: In this qualitative study, a total of 60 of 159 invited clinician-scientists who received National Institutes of Health K08 or K23 awards between 2006 and 2009 and responded to a survey in 2021 agreed to participate. Invitees were selected using random, purposive sampling to support sample heterogeneity. Semistructured in-depth interviews were conducted January to May 2022. For this study, interviews from 31 women were analyzed using the framework approach to thematic analysis. Data analyses were performed between August and October 2023. Main Outcomes and Measures: Descriptive themes of participant experiences of gender and gender-based barriers in academic medicine. Results: A total of 31 women clinician-scientists (8 identifying as Asian [25.8%], 14 identifying as White [45.2%], and 9 identifying as members of a minority group underrepresented in medicine [29.0%]; 14 aged 40-49 years [45.2%] and 14 aged 50-59 years [45.2%]) were included. Among them, 17 participants (54.8%) had children who required adult supervision or care, 7 participants (22.6%) had children who did not require supervision or care, and 6 participants (19.4%) did not have children. There were 4 dominant themes identified within participant experiences in academic medicine: the mental burden of gendered expectations at work and home, inequitable treatment of women in bureaucratic processes, subtle and less subtle professional exclusion of women, and value of communities built on shared identities, experiences, and solidarity. Conclusions and Relevance: This study found that women perceived the institution of academic medicine as a male-centric system misaligned with the needs of women, with associated feelings of exclusion, disillusionment, and loss of trust in their institutions. Findings suggest that the confluence of domestic obligations and unaccommodating institutional environments may make it difficult for women clinician-scientists to achieve established timelines of career progression and productivity; these findings may have long-term implications for the well-being and retention of women in academic medicine.

Rapid auditory and phonemic processing relies on the left planum temporale.

After initial bilateral acoustic processing of the speech signal, much of the subsequent language processing is left-lateralized. The reason for this lateralization remains an open question. Prevailing hypotheses describe a left hemisphere (LH) advantage for rapidly unfolding information-such as the segmental (e.g., phonetic and phonemic) components of speech. Here we investigated whether and where damage to the LH predicted impaired performance on judging the directionality of frequency modulated (FM) sweep stimuli that changed within short (25ms) or longer (250ms) temporal windows. Performance was significantly lower for stroke survivors (n = 50; 18 female) than controls (n = 61; 34 female) on FM Sweeps judgments, particularly on the short sweeps. Support vector regression lesion-symptom mapping (SVR-LSM) revealed that part of the left planum temporale (PT) was related to worse performance on judging the short FM sweeps, controlling for performance on the long sweeps. We then investigated whether damage to this particular area related to diminished performance on two levels of linguistic processing that theoretically depend on rapid auditory processing: stop consonant identification and pseudoword repetition. We separated stroke participants into subgroups based on whether their LH lesion included the part of the left PT that related to diminished short sweeps judgments. Participants with PT lesions (PT lesion+, n = 24) performed significantly worse than those without (PT lesion-, n = 26) on stop consonant identification and pseudoword repetition, controlling for lesion size and hearing ability. Interestingly, PT lesions impacted pseudoword repetition more than real word repetition (PT lesion-by-repetition trial type interaction), which is of interest because pseudowords rely solely on sound perception and sequencing, whereas words can also rely on lexical-semantic knowledge. We conclude that the left PT is a critical region for processing auditory information in short temporal windows, and it may also be an essential transfer point in auditory-to-linguistic processing.

Legal Decision-Making in an Adult Rape Case Involving DNA Evidence.

This study investigated how jurors use deoxyribonucleic acid (DNA) evidence in an adult rape trial with a female victim and a male stranger defendant. Community members read a trial summary and then made case judgments (e.g., verdict). Results showed: (a) DNA evidence led to more pro-victim judgments (e.g., more guilty verdicts) than those who did not receive DNA evidence; (b) women were more pro-victim than men; (c) pro-victim judgments indirectly affected the presence of DNA evidence and verdict; and (d) the reason for a guilty verdict when DNA evidence was present typically noted a focus on the victim and DNA evidence.

Recurrent Peritonsillar Abscess Caused by Vaginal Flora: A Common Problem From a Unique Source.

Peritonsillar abscesses (PTAs) are typically caused by group A Streptococcus or mixed oral flora. Gardnerella vaginalis is a part of the normal vaginal microbiome, and overgrowth can cause bacterial vaginosis. We present a case of recurrent PTA with G. vaginalis superinfection, which occurred after the patient performed oral sex on a female after incision and drainage of her initial PTA. The patient continued to have recurrent PTAs until G. vaginalis was identified, and antibiotic coverage was broadened to cover both group A Streptococcus and G. vaginalis. This case highlights the importance of culturing PTA aspirate for directed antibiosis in persistent or recurrent infections. The rare superinfection also raises the question of advising abstinence from oral-genital contact after oral procedures to minimize risk of superinfection.

Untargeted, tandem mass spectrometry metaproteome of Columbia River sediments.

Rivers are critical ecosystems that impact global biogeochemical cycles. Nonetheless, a mechanistic understanding of river microbial metabolisms and their influences on geochemistry is lacking. Here, we announce metaproteomes of river sediments that are paired with metagenomes and metabolites, enabling an understanding of the microbial underpinnings of river respiration.

Assessing the risk of lumbar degenerative disc disease associated with swimming: A systematic review.

OBJECTIVE: The purpose of the current study is to synthesize the outcomes of investigations reporting the odds of lumbar degenerative disc disease (DDD) in competitive swimmers compared to controls. LITERATURE SURVEY: PubMed, Embase, and Web of Science databases were searched according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines from inception until March 2023 to identify relevant studies evaluating the risk for lumbar DDD associated with swimming. METHODS: Data in the current literature were synthesized for positive imaging findings of DDD at one or more lumbar level in swimmers compared to nonswimmers. Additionally, data regarding prevalence of lumbar disc degeneration and back pain in competitive swimmers were synthesized. SYNTHESIS: Four studies were included in the final analysis. Study quality and risk of bias were deemed adequate. There was significant heterogeneity among studies (I2 = 0.74) regarding data collected, population of swimmers, sample size, and methods. Therefore, a meta-analysis was not conducted. The majority of the studies included in this study (three of four) reported that swimmers have increased odds of developing lumbar DDD. Additionally, secondary outcome analysis indicated that swimmers have a higher probability of developing moderate-to-severe back pain. CONCLUSION: Competitive swimming appears to be associated with the presence of DDD on advanced imaging and moderate-to-severe back pain. These findings are limited by significant differences in study methodology in the included studies. Although swimming is conventionally considered a low-impact sport, elite swimmers risk developing lower back pain and disc pathology, possibly because training involves unique biomechanics with repetitive rotational and hyperextension/flexion of the spine. Further research investigating risk factors involving biomechanics of swimming on the spine may have important implications for stroke technique, injury prevention, and rehabilitation for swimmers.

Clinical Trial Inclusion and Impact on Early Adoption of Medical Innovation in Diverse Populations.

BACKGROUND: Inadequate inclusion in clinical trial enrollment may contribute to health inequities by evaluating interventions in cohorts that do not fully represent target populations. OBJECTIVES: The aim of this study was to determine if characteristics of patients with heart failure (HF) enrolled in a pivotal trial are associated with who receives an intervention after approval. METHODS: Demographics from 2,017,107 Medicare patients hospitalized for HF were compared with those of the first 10,631 Medicare beneficiaries who received implantable pulmonary artery pressure sensors. Characteristics of the population studied in the pivotal CHAMPION (CardioMEMS Heart Sensor Allows Monitoring of Pressure to Improve Outcomes in NYHA Class III Heart Failure Patients) clinical trial (n = 550) were compared with those of both groups. All demographic data were analyzed nationally and in 4 U.S. regions. RESULTS: The Medicare HF cohort included 80.9% White, 13.3% African American, 1.9% Hispanic, 1.3% Asian, and 51.5% female patients. Medicare patients <65 years of age were more likely to be African American (33%) and male (58%), whereas older patients were mostly White (84%) and female (53%). Forty-one percent of U.S. HF hospitalizations occurred in the South; demographic characteristics varied significantly across all U.S. regions. The CHAMPION trial adequately represented African Americans (23% overall, 35% <65 years of age), Hispanic Americans (2%), and Asian Americans (1%) but underrepresented women (27%). The trial's population characteristics were similar to those of the first patients who received pulmonary artery sensors (82% White, 13% African American, 1% Asian, 1% Hispanic, and 29% female). CONCLUSIONS: Demographics of Centers for Medicare and Medicaid Services beneficiaries hospitalized with HF vary regionally and by age, which should be considered when defining "adequate" representation in clinical studies. Enrollment diversity in clinical trials may affect who receives early application of recently approved innovations.

Psychopathology, disordered eating, and impulsivity as predictors of weight loss 24 months after metabolic and bariatric surgery.

BACKGROUND: The relationship between theoretically relevant psychosocial and behavioral variables and outcomes of metabolic and bariatric surgery remains unclear. Some studies have found that the presence of psychopathology, disordered eating, and impulsivity, either before surgery or during the early postoperative period, is associated with suboptimal postoperative weight loss. Other studies have not found these relationships. OBJECTIVE: Examine the relationship between psychopathology, disordered eating, impulsivity, and weight loss 24 months postoperatively. SETTING: Two large, urban university health systems. METHODS: Participant characteristics were collected using validated interviews, patient-reported outcome measures, and computerized assessment methods. Linear mixed effect models were used to test the association of the variables of interest on percent weight loss (%WL). RESULTS: Three hundred participants were enrolled at baseline; weight data at 24 months were available for 227 participants; between 181 and 53 individuals completed other outcome measures. The mean %WL was 23.3 ± 9.9% at 24 months. Patients who underwent Roux-en-Y gastric bypass lost more weight than those who underwent sleeve gastrectomy. The presence of subjective binge episodes at baseline was related to a greater %WL at 24 months; there were no other baseline predictors. The presence of eating disorder diagnoses and disordered eating symptoms after surgery were associated with smaller weight losses over 24 months. Current and lifetime psychopathology and impulsivity were unrelated to %WL at 24 months. CONCLUSION: Disordered eating after bariatric surgery was associated with a smaller %WL at postoperative year 2. Additional monitoring of these symptoms in the early postoperative period is recommended. Psychotherapeutic and/or dietary interventions may promote more optimal weight loss outcomes.

Functional partitioning of sentence processing and emotional prosody in the right perisylvian cortex after perinatal stroke.

In healthy adults different language abilities-sentence processing versus emotional prosody-are supported by the left (LH) versus the right hemisphere (RH), respectively. However, after LH stroke in infancy, RH regions support both abilities with normal outcomes. We investigated how these abilities co-exist in RH regions after LH perinatal stroke by evaluating the overlap in the activation between two fMRI tasks that probed auditory sentence processing and emotional prosody processing. We compared the overlap for these two functions in the RH of individuals with perinatal stroke with the symmetry of these functions in the LH and RH of their healthy siblings. We found less activation overlap in the RH of individuals with LH perinatal stroke than would be expected if both functions retained their typical spatial layout, suggesting that their spatial segregation may be an important feature of a functioning language system.

CAMPER: curated annotations for profiling microbial polyphenol metabolic potential.

Summary: Polyphenols are diverse and abundant carbon sources across ecosystems-having important roles in host-associated and terrestrial systems alike. However, the microbial genes encoding polyphenol metabolic enzymes are poorly represented in commonly used annotation databases, limiting widespread surveying of this metabolism. Here we present CAMPER, a tool that combines custom annotation searches with database-derived searches to both annotate and summarize polyphenol metabolism genes for a wide audience. With CAMPER, users will identify potential polyphenol-active genes and genomes to more broadly understand microbial carbon cycling in their datasets. Availability and Implementation: CAMPER is implemented in Python and is published under the GNU General Public License Version 3. It is available as both a standalone tool and as a database in DRAM v.1.5+. The source code and full documentation is available on GitHub at https://github.com/WrightonLabCSU/CAMPER.

Alternate routes to mnm5s2U synthesis in Gram-positive bacteria.

The wobble bases of tRNAs that decode split codons are often heavily modified. In bacteria, tRNAGlu, Gln, Asp contains a variety of xnm5s2U derivatives. The synthesis pathway for these modifications is complex and fully elucidated only in a handful of organisms, including the Gram-negative Escherichia coli K12 model. Despite the ubiquitous presence of mnm5s2U modification, genomic analysis shows the absence of mnmC orthologous genes, suggesting the occurrence of alternate biosynthetic schemes for the conversion of cmnm5s2U to mnm5s2U. Using a combination of comparative genomics and genetic studies, a member of the YtqA subgroup of the radical Sam superfamily was found to be involved in the synthesis of mnm5s2U in both Bacillus subtilis and Streptococcus mutans. This protein, renamed MnmL, is encoded in an operon with the recently discovered MnmM methylase involved in the methylation of the pathway intermediate nm5s2U into mnm5s2U in B. subtilis. Analysis of tRNA modifications of both S. mutans and Streptococcus pneumoniae shows that growth conditions and genetic backgrounds influence the ratios of pathway intermediates owing to regulatory loops that are not yet understood. The MnmLM pathway is widespread along the bacterial tree, with some phyla, such as Bacilli, relying exclusively on these two enzymes. Although mechanistic details of these newly discovered components are not fully resolved, the occurrence of fusion proteins, alternate arrangements of biosynthetic components, and loss of biosynthetic branches provide examples of biosynthetic diversity to retain a conserved tRNA modification in Nature.IMPORTANCEThe xnm5s2U modifications found in several tRNAs at the wobble base position are widespread in bacteria where they have an important role in decoding efficiency and accuracy. This work identifies a novel enzyme (MnmL) that is a member of a subgroup of the very versatile radical SAM superfamily and is involved in the synthesis of mnm5s2U in several Gram-positive bacteria, including human pathogens. This is another novel example of a non-orthologous displacement in the field of tRNA modification synthesis, showing how different solutions evolve to retain U34 tRNA modifications.

Peripheral neuronal activation shapes the microbiome and alters gut physiology.

The gastrointestinal (GI) tract is innervated by intrinsic neurons of the enteric nervous system (ENS) and extrinsic neurons of the central nervous system and peripheral ganglia. The GI tract also harbors a diverse microbiome, but interactions between the ENS and the microbiome remain poorly understood. Here, we activate choline acetyltransferase (ChAT)-expressing or tyrosine hydroxylase (TH)-expressing gut-associated neurons in mice to determine effects on intestinal microbial communities and their metabolites as well as on host physiology. The resulting multi-omics datasets support broad roles for discrete peripheral neuronal subtypes in shaping microbiome structure, including modulating bile acid profiles and fungal colonization. Physiologically, activation of either ChAT+ or TH+ neurons increases fecal output, while only ChAT+ activation results in increased colonic contractility and diarrhea-like fluid secretion. These findings suggest that specific subsets of peripherally activated neurons differentially regulate the gut microbiome and GI physiology in mice without involvement of signals from the brain.

Perceptual-Auditory and Acoustic Analysis of Breathiness in Cis and Transgender Men and Women.

OBJECTIVE: To verify breathiness in the cisgender and transgender men and women's voices, compare values of acoustic and perceptual indicators of breathiness and fundamental frequency (f0) between groups, and compare them between the voices attributed as female and male. STUDY DESIGN: Cross sectional retrospective study. METHODS: The study was approved by the Research Ethics Committee (4,937,140). Sustained vowel /a/ and continuous speech recordings of 21 cisgender men (CISM), 31 transgender men (TM), 32 cisgender women (CISW), and 31 transgender women (TW) were analyzed. Three judges conducted a perceptive-auditory analysis regarding the degree breathiness, using a visual analog scale, and attributed gender (female or male). The ABI (Acoustic Breathiness Index) was extracted using the PRAAT software (6.1.16). The f0, Harmonic-Noise Ratio (HNR), Voice Turbulence Index (VTI), and Soft Phonation Index (SPI) were analyzed using the Multi-Dimensional Voice Program (KayPentax). RESULTS: The ABI value for CISM was lower than for TM and CISW. CISW had a higher f0 than; TM had a higher f0 than CISM; and TW had a higher f0 than CISM. The groups did not differ for HNR and VTI. Regarding the SPI, CISM had higher values than CISW. Regarding the auditory perception, TM presented more intense breathiness than CISM in the vowel. Regarding gender attribution by voice, the voices CISM and CISW were 100% identified as male and female. On the other hand, in the vowel analysis, 45.2% of the TM voices were perceived as female, and 59.4% of TW voices as male. CONCLUSION: Breathiness occurs differently between groups and the voices perceived as male and female. Even when TM is submitted to the use of testosterone and undergoes vocal changes, the transglottal airflow remains, which is a female characteristic of phonation.

The Association of Pregnancy With Outcomes Among Critically Ill Reproductive-Aged Women: A Propensity Score-Matched Retrospective Cohort Analysis.

BACKGROUND: The maternal mortality rate in the United States is unacceptably high. However, the relative contribution of pregnancy to these outcomes is unknown. Studies comparing outcomes among pregnant vs nonpregnant critically ill patients show mixed results and are limited by small sample sizes. RESEARCH QUESTION: What is the association of pregnancy with critical illness outcomes? STUDY DESIGN AND METHODS: We performed a retrospective cohort study of women 18 to 55 years of age who received invasive mechanical ventilation (MV) on hospital day 0 or 1 or who demonstrated sepsis on admission (infection with organ failure) discharged from Premier Healthcare Database hospitals from 2008 through 2021. The exposure was pregnancy. The primary outcome was in-hospital mortality. We created propensity scores for pregnancy (using patient and hospital characteristics) and performed 1:1 propensity score matching without replacement within age strata (to ensure exact age matching). We performed multilevel multivariable mixed-effects logistic regression for propensity-matched pairs with pair as a random effect. RESULTS: Three thousand ninety-three pairs were included in the matched MV cohort, and 13,002 pairs were included in the sepsis cohort. The characteristics of both cohorts were well balanced (all standard mean differences, < 0.1). Among matched pairs, unadjusted mortality was 8.0% vs 13.8% for MV and 1.4% vs 2.3% for sepsis among pregnant and nonpregnant patients, respectively. In adjusted regression, pregnancy was associated with lower odds of in-hospital mortality (MV: OR, 0.50; 95% CI, 0.41-0.60; P < .001; sepsis: OR, 0.52; 95% CI, 0.40-0.67; P < .001). INTERPRETATION: In this large US cohort, critically ill pregnant women receiving MV or with sepsis showed better survival than propensity score-matched nonpregnant women. These findings must be interpreted in the context of likely residual confounding.